POS1292 GENETIC EVIDENCE REVEALS A CAUSAL EFFECT OF SYSTEMIC SCLEROSIS AND THE RISK OF CARDIOVASCULAR DISEASE
Authors: J. Zhou, H. Y. Zheng, R. L. Zhang, Y. X. Liu, X. Y. Yin, Q. Yu, P. F. He, X. Li, S. X. Zhang
Journal: Annals of the Rheumatic Diseases (2023)

Background Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by microvascular damage, dysregulation of innate and adaptive immunity, and fibrosis in many organs[1]. Observational studies have suggested associations between SSc and cardiovascular diseases (CVD)[2]. However, this association is easily disturbed by confusion and reverse causality. In the study, we used Mendelian randomization (MR) to conduct a study on bidirectional causality to examine the relationship between SSc and CVD. Objectives The study aims to evaluate the connection between SSc and CVD, and further to provide comprehensive CVD assessment and treatment for SSc patients. Methods Summary-level statistical data for SSc were derived from a large meta-analysis of GWAS, including 55,114 cases and 482,295 controls. The summary data for 12 CVD were retrieved from genome-wide association studies (GWAS). In this study, we conducted MR analysis using the random-effects inverse-variance weighted (IVW) method as the primary method. The weighted median approach can yield consistent causal estimates, assessing these genetic variants’ horizontal pleiotropy and heterogeneity using the MR-Egger intercept test and Cochran’s Q test. In addition, we utilized the leave-one-out analysis to detect the robustness and consistency of the results. Results Atrial fibrillation(AF) increased the risk of SSc (IVW:OR = 1.428, 95% CI = 1.101-1.854, p = 0.007). Meanwhile, MR-Egger and weighted median pointed toward a similar direction of effect (weighted median: OR = 1.374; 95% CI=0.987-1.912; p = 0.063; MR-Egger: OR = 1.471, 95% CI=0.905-2.391, p=0.140). In the reverse MR, the results of IVW demonstrated that SSc was negatively correlated with the risk of hypertension after removing abnormal single nucleotide polymorphisms(SNPs) (IVW: OR: 0.996,95%CI: 0.993–1.000, p = 0.036). The heterogeneity test showed no significant heterogeneity among selected instrumental variables(IVs) (Q_p value &gt;0.05) except for miocardial infarction(MI)(MR Egger: Q_p value=0.09974) and AF(MR Egger: Q_pval=0.00010; IVE: Q_pval=0.00021). Moreover, no significant evidence of horizontal pleiotropy was observed for IVs. There was no causal genetic relationship between SSc and other CVDs, such as coronary heart disease, heart failure, and pulmonary embolism. Conclusion We verified that SSc could cause pathological hypertension processes. Furthermore, SSc may be causally impacted by AF. The main mechanism of this causal relationship may be conduction system ischemia and left ventricular systolic failure. References [1]Zhao, M., Wu, J., Wu, H., Sawalha, A. H. &amp; Lu, Q. Clinical Treatment Options in Scleroderma: Recommendations and Comprehensive Review. Clin Rev Allergy Immunol 62, 273-291, doi:10.1007/s12016-020-08831-4 (2022). [2]Ngian, G. S. et al. Prevalence of coronary heart disease and cardiovascular risk factors in a national cross-sectional cohort study of systemic sclerosis. Ann Rheum Dis 71, 1980-1983, doi:10.1136/annrheumdis-2011-201176 (2012). Acknowledgements: NIL. Disclosure of Interests None Declared.